Molecular modeling studies will be used to examine the structure and mechanism of activity of the thyroid hormone-activating and -inactivating family of iodothyronine deiodinases (Dio). A thorough understanding of the binding of thyroid hormone derivatives at the molecular level is needed for the design of inhibitors that are specific to this important class of enzymes. In order to facilitate high-throughput molecular mechanics (MM) molecular dynamics (MD) simulations of these selenoproteins and the binding of the iodothyronine substrates and competitive inhibitors, new force field parameters will be developed to describe the halogen bonding interactions proposed for these systems based upon previous work by the PI. Multiple microsecond length MM MD simulations will be used to equilibrate the protein intermediates to determine the role of active site residues in selectivity and to prepare the system for modeling of the deiodination mechanism using hybrid quantum mechanical-molecular mechanical molecular dynamics (QM/MM MD) simulations. Initial studies suggest that a loop conserved in Dio serves as a gating mechanism for substrate binding. A collaboration with U. Schweizer (Universitt Bonn) has been established to corroborate the computational results through experimental studies of proteins incorporating mutations of key residues identified by molecular modeling. This R15 Academic Research Enhancement Award (AREA) proposal will train one graduate student and 3-6 undergraduate students per year in the application of computational methodology to medicinal inorganic chemistry and give opportunities for these students to participate in collaborative research with experimentalists. Infrastructure for biomedical research at ODU will be improved by expanding and upgrading the university Turing High Performance Cluster with high-end graphics processing unit nodes.